Independent roles of prostaglandins and the renin-angiotensin system in abnormal vascular reactivity in Bartter's syndrome

Independent Roles of Prostaglandins and the Renin-Angiotensin

System in Abnormal Vascular Reactivity in Bartter’s Syndrome

TOSHIRO FUJITA, M.D.

KATSUYUKIN ANDO, M.D.

YUJI SATO, Ph.D.

KAMEJIRO YAMASHITA, M.D.

Ibaraki. Japan

MASAYUKIN NOMURA, M.D.

TOSHIO FUKUI, M.D.

Tokyo, Japan

From the Department of Internal Medicine, Insti- tute of Clinical Medicine, University of Tsukuba, Ibaraki, and Municipal Ida Hospital, School of Medicine, Keio Llniverstty, Tokyo, Japan. Requests for reprints should be addressed to Dr. Toshiro Fujtt, Department of Internal Medicine, Universky of Tsukuba, Nllharigun, lbaraki-ken 305, Japan. Manuscript accepted December 21, 1981.

To clarify the independent roles of prostaglandins and the renin- angiotensin system in the pressor resistance to angiotensin II in Bartter’s syndrome, the pressor responsiveness to exogenous angiotensin II was investigated in three patients with the syndrome during the administration of indomethacin and captopril. Indo- methacin is an inhibitor of prostaglandin synthesis, and captoprfl is an angiotensin-converting enzyme inhibttor. All the patients showed high plasma renin activity, increased urinary excretion of prostaglandin E, and pressor resistance to angfotensin II. An analogue of angiotensin II that had weak agontstic properties induced a marked fall in blood pressure. Pretreatment with indomethacin( 150 mg/day) decreased basdine plasma renin activity and reversed the hypo- tensive effect of the anatogue of angfotensfn II. Apparently, our data support the concept that pressor resistance uftimatety results from the increase in the concentration of endogenous angiotensin II. However, the augmentatton of the pressor response to angiotensin II with the admtnistration of indomethacin was signtfk@y (p <O.Ol greater in magnitude than the response obtained with captopril, although the concentration of plasma angiotensin II prior to each infusion of angiotensin II was the same. This observation could be explained by the findtng that indomethacin suppressed both systems, but captopril inhibited only the renin-angtotenstn system. Evktence presented herein suggests that the abnormalities in the vascular reactivity to angiotensin II may result from, not only the decreased number of receptor sites as a result of the increased concentration of endogenous angiotensin II, but also from the alteration of the end-organ sensitivity to angiotensin II via overproduction of prostaglandins.

[ 2-41.

PROSTAGLANDINS AND BARTTER’S SYNDROME-FUJITA ET AL.

TABLE I Clinical Characteristics of Three Patients with Bartter’s Syndrome

Patient No. Normal 1 2 3 Values

Age Sex Blood pressure on admission (mm Hg) Plasma K (mEq/liter) Plasma Na (mEq/liter) Plasma HC03 (mEq/liter) Supine PRA (nglmllhr) Supine PAC (ngldl) Pressor dose of All (ng/kg/min)* Maximum fraction CHZo/CHzO -t Cc, (%) Juxtaglomerular hyperplasia

38 44 54 F M F

124180 122172 118176 2.2 3.0 2.3 3.5-5.0 138 140 138 135-145 34 30 36 24-28

5.0-52 7.2-42 6.2-48 0.4-2.2 14-26 16-32 18-30 2-16

60 50 42 6.8 f 1.0 60 42 58 85-95 + + + -

l An amount of angiotensin II (All) which caused a sustained elevation of diastolic blood pressure by 20 mm Hg above the average control values [ 181. PRA = plasma renin activity; K = potassium; Na = sodium; HCOs = bicarbonate ion; PAC = plasma aldosterone concentration: i- = present; - = absent.

insensitivity to angiotensin II could be attributed to the development of tachyphylaxis to high circulating levels of angiotensin II [ 61.

In the patients receiving an inhibitor of cycloxyge- nase, such as indomethacin or ibuprofen, whose responsiveness to the pressor action of angiotensin II was followed up, normal sensitivity returned [7-141. This suggests that initial resistance is related either directly or indirectly, to prostaglandin production [ 15171. It may relate to the initial increased concentration of plasma bradykinin (which also decreased with the treatment) [ 121. Alternatively, the prostaglandin E in blood vessel walls may, like renal prostaglandin E, ov- erproduce in patients with Bartter’s syndrome, before treatment is initiated. However, the baseline concentration of plasma angiotensin II was lowered to normal with the administration of indomethacin. As a result, it is possible that the augmented response to angiotensin II achieved with indomethacin is due to a lower endogenous renin activity per se, rather than due to the inhibition of overproduction of prostaglandins.

The present study was carried out, to test the independent roles of prostaglandins and the renin-angiotensin system in the vascular insensitivity to angiotensin II seen in Bartter’s syndrome. The pressor responsiveness to exogenous angiotensin II was investigated in three patients with the syndrome, during inhibition of prostaglandin production with indomethacin and during blockade of the renin-angiotensin system with captopril.

PATIENTS AND METHODS

The clinical data of three adult subjects who presented with hypokalemic alkalosis, secondary aldosteronism, and normal blood pressure are shown in Table I. There was no history of vomiting or gastrointestinal disease, and abuse of laxatives and diuretics was denied. Function of the liver and kidneys,

as judged by routine laboratory methods, urinalysis, endogenous clearance of creatinine, and intravenous urography were unremarkable. A subnormal pressor response was observed after administration of IO-minute infusions of angiotensin II (Hypertensinw, CIBA), at successive dosages of 5, 10, 20, 35, 50, 75, and 100 ng/kg/min until an amount was reached that caused a sustained elevation of diastolic blood pressure by 20 mm Hg above the average control values [ 181. In all three patients, histologic examination revealed hyperplasia of the juxtaglomerular apparatus. As reported by Fujita et al. [ 191 and Gill et al. [20], the occurrence of Battter’s syndrome is associated with a decrease in fractional chloride and sodium reabsorption in the thick ascending limb of the loop of Henle, which was measured by the fraction CH20 (free-water clearance)/[CHzo -I- Cc, (chloride clearance)] under conditions of maximum free-water diuresis. Protocol. The patients were admitted to our hospital and adhered to a diet which contained 150 mEq of sodium and 60 mEq of potassium per day. After a five-day control period, the study was started. The administration of all medications was discontinued, except for potassium substitution, which was administered whenever it was clinically necessary.

The angiotensin II analogue ([Sar’-lIeua]-angiotensin II) was administered by a constant infusion for 30 minutes at a fixed rate of 300 nglkglmin. The infusion was repeated during the administration of indomethacin (150 mg/day), which had been started three days previously. Each patient received the last dose (50 mg) of indomethacin immediately prior to infusion of angiotensin II.

Angiotensin II was administered before and after the treatment with indomethacin. The infusion of angiotensin II was preceded by the intravenous administration of 5 percent dextrose for 15 minutes. The dosage of angiotensin II (5, 10, 50, 100 ng/kg/min) was increased every 15 minutes until a rise in diastolic blood pressure of at least 20 mm Hg was observed. Blood pressure was measured by cuff sphygmo- manometer every 2 minutes in the preinfusion period and during the administration of angiotensin II. Diastolic blood pressures at each dose level were calculated by averaging the previous three or four determinations.

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Captopril, an oral angiotensin-converting enzyme inhibitor, was orally administered in a single dose (25 mg) 90 minutes before infusion of angiotensin II began; at that time blood pressure stabilized. In the preliminary study (Patients 1 and 2), after just falling, blood pressure stabilized for a period of between 45 minutes and 180 minutes after the oral administration of captopril. Hormonal Determinations. Blood for hormonal determinations was drawn when patients were in the supine position before administration of both indomethacin and captopril and immediately prior to infusion of angiotensin II after the treatments. Plasma renin activity was determined in peripheral venous blood, by radioimmunoassay of angiotensin I, generated during incubation of plasma at pH 6.5 and 37%. Plasma angiotensin II concentration was measured by the radioimmunoassay technique [21]. Plasma aldosterone concentration was quantitated by the radioimmunoassay technique using a commercial kit (CEA-IRE-SORIN). Urinary prostaglandin E was measured radioimmunologically by the modified method of Aulletta et al. [22], as described in a

PreViOUS study [ 231. A 2 ml aliquot of urine, to which 1,000 cpm of 3H-prostaglandin B1 (PGB,) had been added (to monitor recoveries), was adjusted to a pH between 3.5 and 4.5 with 1.0 N hydrochloric acid. Neutral lipids were extracted with redistilled ethyl acetate. The extracts were partially purified by the “mini-silicic acid” column [24]. The prostaglandin E fraction was eluted with a mixture of benzene ethyl acetate and methanol (60:40:4). The prostaglandin E fraction was converted to prostaglandin B with alkaline treatment [25], and measured radioimmunologically with prostaglandin B1 antiserum (CA-501, Clinical Assay). The overall recovery rate of prostaglandin E was 52 f 3 percent (mean f SEM). The data were corrected for individual recoveries. StatistIcal Analysis. Student unpaired and paired t tests were used to determine statistical significance of differences between groups and paired observation. Results are ex- pressed as mean f SEM and were considered significant at p <0.05.

RESULTS

Effects of Indomethacin upon the Response to An- giotensfn II Anatogue ([Sar’-lIeus]-Angiotensin II). During infusion of angiotensin II analogue but before treatment with indomethacin there was a marked drop in blood pressure; maximum decrement of mean blood pressure was -24 mm Hg, - 12 mm Hg, and -24 mm Hg, in Patients 1, 2, and 3. respectively. After the administration of indomethacin, however, the infusion produced a paradoxic rise in blood pressure, while baseline plasma renin activity decreased from a control value of 30.2 f 3.0 to 3.1 f 0.3 ng/ml/hr with indomethacin. The indomethacin-dependent improvement in the blood pressure response to the angiotensin II analogue for the three patients is shown in Figure 1. Effects of lndomethacin and Captopril on the Pressor Reeponee to Angiotenein II. lndomethacin decreased plasma renin activity significantly from a control value of 21.5 f 1.7 ng/ml/hr to 2.7 f 0.3 ng/ml/hr (p <O.Ol).

B llO-

E

%I 100.

5

r”

90.

.c 80-

a,

z m-

5

60-1

~&j 300nglKglmin

* ;

t I I 1 -10 0 10 2’0 ab a0 50

Minutes

F&It? 1. Effect of an analogu? of an&tensin II uoon mean blood pressure (mean f SE&$ in three-ptients w& &utter’s syndrome prior to (a) and during (0) treatment with indomethacin. Star indicates p < 0.05 versus control.

Urinary excretion of aldosterone decreased from a control value of 24 f 10 pg/day to 18 f 8 pglday (not significant). Body weight was significantly increased (1.7 f 0.4 kg). Urinary excretion of prostaglandin E was 62 f 18 ng/hr, more than two-fold greater than that in healthy adult subjects (26 f 9 ng/hr), when fed a diet containing 150 mEq of sodium/day, and indomethacin reduced urinary prostaglandin E by 52 percent to 30 f 8 ng/hr. On the other hand, during the administration of captopril, plasma renin activity was significantly increased to 162 f 28 ng/ml/hr (p <O.OS) and plasma akfosterone concentration was significantly decreased from 28.2 f 2.0 to 18.2 f 1.8 ng/dl (p 40.05). Plasma angiotensin II concentrations before the treatments were elevated: 160 f 24 pg/ml before the administration of indomethacin and 172 f 30 pgJml before the administration of captopril. Both indomethacin and captopril significantly reduced plasma angiotensin II to 48.4 f 5.4 and to 42.2 f 7.8 pg/ml, respectively (both p <0.05), indicating that the concentration of plasma angiotensin II immediately prior to the infusions of angiotensin II was the same.

Mean blood pressure did not change with the administration of indomethacin. On the other hand, it markedly decreased with captopril, and 45 minutes later, it became stable. At that point, the infusion of angiotensin II was started. The dose of angiotensin II required to produce an increase of 20 mm Hg in diastolic blood pressure during the control period was 50 f 5 ng/kg body weight/min. These dosages are much higher than those required to produce the same response in healthy subjects (6.8 f 1.0 ng/kg body weight/min [ 181. During administration of indomethacin,

July 1982 The Am&can Journal of Medicine Volume 73 73


t

lndomethacin

5::

Control

I I I 1 5 10 50 100

Angiotensin n (nglKg/min)

Figure 2. Angiotensin II pressor responses (increment of diastolic blood pressure; mean f SEM) in three patients with Butter’s syndrome during the control period (O), during inhibition of prostaglandin synthesis with indomethacin (O), and during angiotensin-converting enzyme blockade with captopril (A). Closed star indicates p < 0.05 versus control, and open star, p < 0.05 versus captopril.

the dose of angiotensin II required to produce an increase of 20 mm Hg in diastolic blood pressure (7.8 f 2.0 nglkg body weight/min) was decreased by 84 percent; that is, to a virtually normal dose. During administration of captopril, however, the dose of angiotensin II required to produce an increase of 20 mm Hg in diastolic blood pressure was decreased by only 52 percent (24 f 4 ng/kg body weight/min which was significantly (p <O.Ol) higher than it was during the administration of indomethacin. The dose-response curves of diastolic blood pressure to angiotensin II for the three patients during the three periods are shown in Figure 2. With each dose of angiotensin II, the greatest increase in diastolic blood pressure was seen during the period of treatment with indomethacin; a significantly greater increase in diastolic pressure was found during the period of treatment with captopril than that during the control period (p <O.Ol). Thus, as is illustrated, the shift of the dose-response curve to the left with indomethacin is greater in magnitude than that with captopril.

COMMENTS

A prominent feature of Bartter’s syndrome is the resistance of exogenous angiotensin II to the pressor action. In the original descriptions of the syndrome, the decreased sensitivity of blood pressure to angiotensin II was attributed to a defect in arterial smooth muscle.

This defect was postulated to be a proximal cause of the syndrome [ 11. Other investigators attributed the vascular insensitivity to the development of tachyphylaxis to angiotensin II [6]. However, tachyphylaxis to angiotensin II does not adequately explain why many patients with the syndrome also exhibit resistance to the vasoconstrictor action of norepinephrine [ 26,271. Therefore, the pathogenesis of abnormal vascular reactivity in Bartter’s syndrome has been controver- sial.

It has been demonstrated that angiotensin responsiveness in Bar-her’s syndrome can be improved and even normalized following renin-lowering maneuvers, including infusion of albumin [20,28], saline loading [ 291, prostaglandin synthetase inhibition [ 9,11,13], and administration of propranolol [9]. This finding suggests that improved angiotensin responsiveness results from manuevers which decrease the concentration of plasma renin with a resultant decrease in the concentration of plasma angiotensin II. Therefore, previous investigators postulated that the attenuated vascular reactivity resulted from tachyphylaxis to high circulating levels of angiotensin II. This theory is based on the concept that there is an inverse relationship between the circulating concentration of plasma angiotensin II and the pressor response to exogenous angiotensin II, which some researchers attributed to a decrease in available angiotensin II receptor sites because of prior occupancy of these sites by endogenous angiotensin II [30]. Other researchers attribute this concept of an inverse relationship to an absolute decrease in the number of receptor sites as a result of an increase in concentration of endogenous angiotensin II [31], which is similar to what has been reported with other peptide hormones [5]. According to this theory, the improved responsiveness to exogenous angiotensin II during administration of indomethacin might have resulted from decreased levels of endogenous angiotensin II. Indeed, this phenomenon might account to some extent, for the increased responsiveness to exogenous angiotensin II during administration of indomethacin. In the present study, however, during the administration of captopril, an oral angiotensin-converting enzyme inhibitor, the pressor response to exogenous angiotensin II was moderately enhanced but was still subnormal, despite decreased concentration of circulating angiotensin II. Since concentrations of plasma angiotensin II were the same in both periods, the data suggest that the observed normalization of the pressor response to angiotensin II with the administration of indomethacin could not be fully explained solely by the increased number of receptor sites [31] or by the decreased number prior to receptor occupancy [30] as a result of the decreased concentrations of circulating angiotensin II. Therefore, we suggest that administration of indomethacin may

74 July 1982 The American Journal oi Medlclne Volume 73


have increased the responsiveness to exogenous an- contractions induced by the angiotensin II infused might giotensin II in patients with Bartter’s syndrome, not only be suppressed partly by the indomethacin induced in- by decreasing plasma renin activity, with a consequent hibition of prostaglandin production stimulated in the decrease in concentration of plasma angiotensin II, but vessel walls. Moreover, sodium retention during treat- also as a result of the inhibition of the vasodilator effects ment with indomethacin could induce alteration of of prostaglandins on blood vessels. Accordingly, the end-organ sensitivity to exogenous angiotensin II, thus explanation for the marked fall in blood pressure during resulting in positive cooperation [35]. Therefore, ad- the administration of a competitive inhibitor of angio- ministration of indomethacin could enhance the pressor tensin II can be that it is a result of the excess amount responsiveness to angiotensin II by the inhibition of of prostaglandins, in addition to the increased con- endogenous prostaglandin production. This effect might centration of circulating angiotensin II. During treatment operate through a change in some of the following with indomethacin, the angiotensin II analogue might mechanisms: affinity or character of angiotensin II re- exhibit agonistic action partly because of the inhibition ceptors, membrane potentials, calcium movement, or of prostaglandin synthesis within the vessel walls. contractile proteins.

Prostaglandins of the E series and PG12 have been shown to blunt the response of vascular smooth muscle to the administration of angiotensin and norepinephrine [32]. In turn, these vasoconstrictors are also capable of stimulating prostaglandin production [33]. McGiff and Vane [34] have proposed the possibility that the ulti- mate effect of angiotensin or norepinephrine on vascular resistance depends on a balance between the degree of smooth muscle contraction induced and the amount of prostaglandin produced due to stimulation in the vessel wall. Thus, in the present study, the pressor response to exogenous angiotensin II was augmented by indomethacin therapy, possibly because the prostaglandin-induced attenuation of the smooth muscle

In summary, in three patients with Barber’s syndrome who had increased urinary excretion of prostaglandin E, the administration of indomethacin improved pressor responsiveness to exogenous angiotensin II, possibly not only because of the increased number of receptor sites, via a decrease in concentration of plasma angiotensin II, but also as a result of the inhlibition of the vasodilator effects of prostaglandins on blood vessels. The results of this study support the recent concept that insensitivity to exogenous angiotensin II and mainte- nance of normal blood pressure in Bartter’s syndrome may result from an increased synthesis of the vasodilator substance, prostaglandin E or prostacyclin, by blood vessel walls [ 161.

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Independent roles of prostaglandins and the renin-angiotensin system in abnormal vascular reactivity in Bartter's syndrome